1. Field of the Invention
The present invention relates to a composition for the prevention and treatment of cell proliferative disease including cancer which comprises ethyl(2-methyl-3{(E)-[(naphtho[2,1-b]furan-2-ylcarbonyl)hydrazono]methyl}-1H-indole-1-yl)acetate, the analogs thereof, or the pharmaceutically acceptable salts thereof as an active ingredient. More particularly, the present invention relates to a compound that can induce apoptosis by depolymerizing microtubules and can have an effect on multi-drug resistant cancer cells.
2. Description of the Related Art
Microtubule is a major component of cytoskeleton, which is composed of tubulin heteropolymer comprising α subunit and β subunit. Microtubule is involved in a variety of cellular functions such as intracellular transportation, maintaining polarity, intracellular signal transduction, cell migration, and cell proliferation, etc. In the course of mitosis, spindle fibers are generated and chromosomes are arranged in the center of cell to be separated later to the opposite side ends. When the spindle fiber is not functioning well, cell division is suppressed, resulting in apoptosis. So, microtubule is in the center of cancer research as a major target of an anti-cancer agent.
Drugs targeting microtubule are largely divided into two groups; one is the drugs playing a role in stabilizing microtubule and the other is the drugs playing a role in instabilizing microtubule. Taxane, pacilitaxel (Taxol), and decetaxel are the microtubule stabilizers playing a role in preventing depolymerization of microtubule and rather working on strengthening the polymerization. Most of the microtubule stabilizers are conjugated to taxane binding site or β-tubulin overlapping site. Microtubule destabilizer is exemplified by cholchicine and vinca alkaloid, which is binding to cholchicine or vinca binding site. The drug that shows pharmaceutical effect at a lower concentration is the drug targeting microtubule itself rather than the drug affecting microtubule polymer. However, both drugs suppress mitosis equally.
The drugs specifically targeting microtubule, that have been used clinically nowadays, are pacilitaxel and vinca alkaloid. However, these drugs have a problem of low efficacy because of the acquired resistance and the congenital resistance of cancer cell. Drug resistance is closely related to the expression of the protein involved in multi-drug resistance such as P-glycoprotein (P-gp). Resistance can also be induced by the change or mutation of tubulin isotype. Besides, because of the high toxicity (particularly neurotoxicity) of a tubulin inhibitor, researchers hesitate in developing a tubulin inhibitor. Therefore, recent studies have been focused on the development of a novel tubulin inhibitor that has a low neurotoxicity and is not affected by the mechanisms of anticancer drug resistance.
Thus, the present inventors screened the materials capable of inhibiting cell proliferation from small-molecule library in order to identify a therapeutic material effective in treating cell proliferative disease. As a result, the inventors confirmed that ethyl(2-methyl-3-{(E)-[(naphtho[2,1-b]furan-2-ylcarbonyl)hydrazono]methyl}-1H-indole-1-yl)acetate and the analogs thereof could suppress mitosis significantly, so that the compound could be effectively used for the composition for treating cell proliferative disease including cancer, leading to the completion of this invention.